Hydrogen-bonded dimers in dipyrrinones and acyldipyrrinones

Article abstract of DOI:10.1007/s007060170131

A crystal structure determination of the 9-acyl-dipyrrinone 9-butanoyl-2,3,7,8-tetramethyl-(10H)-dipyrrin-1-one indicates the presence of intermolecularly hydrogen-bonded dimers; however, in CHCl₃ solution the pigment is monomeric as determined by vapor pressure osmometry measurements. Lacking an alkyl group at C(8), the 9-acyl-dipyrrinone exhibits only a weak tendency to form dimers in CHCl₃ (K_A ～ 60 M^-1) as determined by analysis of variable temperature ¹H NMR data. In contrast, when the 9-acyl group is replaced by formyl or when the acyl group is fixed in a syn orientation to the pyrrole NH, the dipyrrinone is strongly prone to dimerization in CHCl₃.

Full text of DOI:10.1007/s007060170131

Monatshefte fuÈr Chemie 132, 203±221 (2001)
Hydrogen-Bonded Dimers in Dipyrrinones
and Acyldipyrrinones
Ã
Michael T. Huggins and David A. Lightner
Department of Chemistry, University of Nevada, Reno, NV 89557-0020, USA
Summary. A crystal structure determination of the 9-acyl-dipyrrinone 9-butanoyl-2,3,7,8-
tetramethyl-(10H)-dipyrrin-1-one indicates the presence of intermolecularly hydrogen-bonded
dimers; however, in CHCl3 solution the pigment is monomeric as determined by vapor pressure
osmometry measurements. Lacking an alkyl group at C(8), the 9-acyl-dipyrrinone exhibits only a
weak tendency to form dimers in CHCl3 (KA ꢀ 60 M 1) as determined by analysis of variable
temperature 1H NMR data. In contrast, when the 9-acyl group is replaced by formyl or when the acyl
group is ®xed in a syn orientation to the pyrrole NH, the dipyrrinone is strongly prone to dimerization
in CHCl3.
Keywords. Pyrrole; X-Ray structure; Hydrogen bonding; Vapor pressure osmometry.
Introduction
Dipyrrinones [1] are yellow chromophores found in nature as components of
bilirubin (Fig. 1), the pigment of jaundice. They are known to be apprecatious
participants in hydrogen bonding, both in the crystal [2±4] and in solution [4±8].
Using vapor pressure osmometry (VPO), Falk et al. [1, 6a] ®rst showed that
kryptopyrromethenone (Fig. 2A) is dimeric in CHCl3. This conclusion was
1
reaf®rmed subsequently by analyzing the concentration dependence of the NH H
NMR chemical shifts of the dipyrrinone in CDCl3 [8c]. The dimer, which is planar
and intermolecularly hydrogen-bonded, exhibits lactam and pyrrole NH chemical
shifts at 11.42 and 10.44 ppm at 22ꢁC, whereas the monomer's NH chemical shifts
appear at 7.75 and 8.10 ppm. The association constant of kryptopyrromethenone is
rather large (KA ꢀ 23000 at 22ꢁC) [8c]. In contrast, in the polar, hydrogen-bonding
solvent (CD3)2SO, dipyrrinones are apparently monomeric and hydrogen-bonded to
solvent [8b], and the lactam and pyrrole NH chemical shifts again differ: 9.83 and
10.22 ppm, respectively. Dipyrrinone dimerization, with stabilization by hydrogen
bonds, is thus apparently strongly preferred in nonpolar solvents. Even when the
dipyrrinones are components of a larger molecule, such as bilirubin dimethyl ester
or etiobilirubin-IVꢀ (Fig. 1A), the pigments are dimeric in chloroform [1, 6b, 8a].
However, the available evidence suggests that neither bilirubin dimethyl ester nor
etiobilirubin-IVꢀ are dimeric in (CD3)2SO [1, 8a, b].
Ã
Corresponding author

204
M. T. Huggins and D. A. Lightner
Fig. 1. Linear representations of bilirubin and etiobilirubin-IVꢀ, each with two dipyrrinone
chromophores
Fig. 2. (A) Kryptopyrromethenone (5) and its intermolecularly hydrogen-bonded planar dimer; (B)
9-acyl-dipyrrinone with the acyl group in a syn-orientation that might yield dimer-destabilizing
nonbonded electronic repulsions between the lactam C=O and acyl C=O groups; (C) 9-acyl-
dipyrrinone with the acyl group in an anti-orientation that might produce NOEs between the C(2)
CH3 and R groups
Intrigued by the apparently rather strong tendency of dipyrrinones to establish
intermolecular hydrogen bonds in nonpolar solvents, we attempted to perturb the
stability of the dimers by introducing an acyl group at C(9). If the acyl carbonyl of
one dipyrrinone were oriented toward the lactam carbonyl of the companion
dipyrrinone in the dimer, electrostatic repulsions might weaken the dimer. However,
if the alkyl fragments of the acyl group in one dipyrrinone were oriented toward the
C(2) methyl of the second dipyrrinone, this too might destabilize the dimer.
Accordingly, in the following we explore the in¯uence of an acyl group at C(9) on
intermolecular association and hydrogen bonding in a set of dipyrrinones (1±10)
using NMR spectroscopy and VPO (vapor pressure osmometry) measurements.

Dimeric Dipyrrinones
205
Results and Discussion
Synthesis
9-Acyl-dipyrrinones 1±3 were prepared (Scheme 1A) in acceptable yields (35±60%)
by Friedel-Crafts acylation of the appropriate parent 9-H-dipyrrinone with butanoyl
chloride in CH2Cl2 using anhydrous AlCl3 as catalyst. 9-Formyl-dipyrrinone (4)
was prepared in 82% yield from the parent dipyrrinone-9-carboxylic acid (6) by
reaction ®rst with TFA to decarboxylate, then with triethyl orthoformate. All of the
precursor 9-H-dipyrrinones (6, 8, 9) were prepared by decarboxylation of the
Scheme 1.aCe(NH4)2(NO3)6; b4 M aq. KOH, MeOH, re¯.; cmolten KOAc/NaOAc/Á; dbutanoyl
f
i
chloride/AlCl3, CH2Cl2; e(EtO)3CH, CH2Cl2/TFA; EtOH re¯.; gSOCl2; hMg(OEt)2; Zn/HOAc;
jMeOH-H2SO4; TFA
k

206
M. T. Huggins and D. A. Lightner
corresponding dipyrrinone-9-carboxylic acids (12±14) that had been prepared by a
standard base-catalyzed dipyrrinone-forming condensation reaction of either 3,4-
dimethyl-, 3,4-diethyl-, or 3-methyl-4-ethyl-pyrrolinone and a pyrrole ꢁ-aldehyde.
The acyl-dipyrrinone with a fused cyclohexanone ring (10) was prepared in 60%
yield by treatment of the methyl ester of the 9-H-dipyrrinone with a C(8) butanoic
acid chain (19) with TFA. Dipyrrinone 19 was prepared from glutaric anhydride as
outlined in Scheme 1B.
Constitution
The structures of the various dipyrrinones discussed in this paper follow from the
method of synthesis (Scheme 1) and are con®rmed by their 13C NMR spectra (Table
1). Kryptopyrromethenone (5) [6a] 9-H-dipyrrinones 7 [9] and 11 [10] are known
from previous work. Allowing for differences in substituents and substitution
Table 1. Dipyrrinone 13C NMR chemical shifts and assignments; all measurements were made in
CDCl3 at ꢀ10 2 M chemical shifts (ꢂ) reported in ppm down®eld from (CH3)4Si and referenced to the
residual CHCl3 located at 77.00 ppm; carbon assignments are made from HMBC and HMQC
experiments; superscripts denote carbon atoms in sequence (see Ref. [1])
1
11
2
8
3
9
4
6
7
10
1
173.66 172.3
136.25 118.5
141.92 141.5
128.12 131.6
173.65 174.14 174.00 174.34 174.12 174.46 174.10 173.82
134.81 129.32 134.96 123.45 138.71 130.41 129.97 136.56
147.29 148.08 147.72 148.53 141.99 142.63 148.12 141.82
132.99 128.40 127.61 128.40 136.82 129.90 127.48 128.24
2
3
4
5
97.14
98.14
96.79 101.19
96.66 101.08
95.65 101.36 103.19 95.84
6
131.18 124.5
128.94 124.1
123.73 122.0
126.04 120.1
131.08 124.32 130.85 124.22 130.57 126.00 129.41 137.82
123.92 125.09 123.92 125.16 130.19 123.83 115.88 133.00
118.62 111.20 118.45 111.20 128.42 124.49 109.91 129.29
133.07 122.57 132.99 122.60 132.72 120.54 123.34 121.06
7
8
9
91
92
93
94
21
22
31
32
71
72
81
82
190.41
42.09
17.93
13.98
8.59
±
±
±
190.51
40.11
19.19
13.80
16.87
13.99
17.74
±
190.44
40.09
19.16
13.99
8.38
±
±
177.23
±
±
±
188.76
21.75
24.68
30.93
8.64
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
8.57
±
16.99
13.83
17.80
8.06
±
8.66
±
10.18
±
17.00
13.81
17.72
15.71
±
9.88
±
9.36
±
17.90
14.57
11.53
±
17.99
14.94
11.57
±
9.93
±
8.52
±
9.27
±
15.47 15.85
11.53 11.54
9.44
±
9.83
±
17.36
17.11
17.11
16.27
18.47
17.94
16.78
15.10
9.94
±
±
±
±
±
±
±
±
11.66
±
10.26
±
±
±
±
±
±
±
±
±

Dimeric Dipyrrinones
207
pattern, 9-H-dipyrrinones 6±9 show the expected 13C NMR chemical shifts.
Conversion of the 9-H-dipyrrinones 6, 8, 9, and 11 to the corresponding 9-butanoyl
or 9-formyl derivatives leads to new carbon signals characteristic of the butanoyl
group and to interesting shifts in the dipyrrinone ring carbons. Thus, as expected,
C(9) shifts down®eld in 1±4 relative to C(9) in 11, 8, 9, and 6; however, C(8) is not
much affected. Interestingly, the chemical shift of remote C(2) is also strongly
deshielded by a carbonyl group on C(9), whereas C(3) is scarcely affected. Ring
carbons 6 and 8 are relatively more deshielded in 1±4 than in 11, 8, 9, and 6, but
bridging carbon 5 is more shielded.
Curiously, C(4) is more deshielded in 2 and 4 than in 8 and 6, but it is more
shielded in 1 and 3 than in 11 and 9. This is particularly odd because 2 and 3 (and 8
and 9) differ only in a methyl or ethyl substituent at C(2).
Constraining the acyl carbonyl into a 6-membered ring, where it is forced to be
syn to the pyrrole NH, has a strong effect on the dipyrrinone pyrrole ring carbon
chemical shifts. Carbon-9 is more shielded by ꢀ 5±12 ppm in 10 relative to C(9) in
1±4, but carbons 6±8 are more deshielded.
Molecular geometry and hydrogen bonding in the crystal
The only reported dipyrrinone crystal structures reported so far [1, 2] had been
obtained from three different dipyrroles, none of which had a 9-acyl group. All three
exhibited intermolecular hydrogen bonding and dipyrrinone pairing in the crystal as
in the example of Figure 2A. Triclinic 9-butanoyldipyrrinone (1) is no exception,
and it too appears as a planar hydrogen-bonded dimer in the crystal (Fig. 3A). The
individual dipyrrinone units are planar, with a syn-(Z) con®guration at C(4)=C(5)
and a C(4)=C(5)±C(6)±N(2) torsion angle of 3.5ꢁ. Distances between molecules A
and B of the dimer are best represented by nonbonded distances in the hydrogen
Ê
Ê
bonding region: N(2A) to O(1B) ˆ 3.044 A and N(1A) to O(1B) ˆ 2.765 A. These
Ê
nonbonded distances are close to the sum (2.90 A) of the van der Waals radii of N
(1.50 A) and O (1.40 A). The acyl group also adopts the sp stereochemistry relative
to the dipyrrinone moiety, with an N(2)±C(9)±C(10)=O(2) torsion angle of 3.8ꢁ.
Ê
Ê
Ê
Layers of dimers stack in the crystal with interplanar distances of ꢀ 3.5 A (Fig. 3B).
Interestingly, whereas 1 prevails in the syn-acyl conformation illustrated in Fig. 2B,
it still prefers to be a dimer in the crystal.
Molecular geometry and hydrogen bonding in solution
Dipyrrinones alkylated at the ꢃ-positions generally adopt a syn-(Z) stereochemistry
1
as the most stable conformation [1]. As revealed by H{1H} NOE experiments in
CDCl3, the 9-acylated dipyrrinones (1±3, 10) and 9-formyl dipyrrinone (4) are no
exception. Thus, as indicated in Fig. 4, NOEs are observed between the lactam and
pyrrole NHs in 1±4 and 10, and between the C(5)±H and the C(4) and C(7) alkyls.
Similar sorts of NOEs have been reported previously for 5 [8c]. Most interestingly,
an NOE is observed between the pyrrole NH and the ꢁ-CH2 of the butanoyl chain of
1, suggesting differing conformations of the acyl group in solution and in the
crystal. Curiously, the same NOE was absent in 2 and 3, but an NOE was detected
between the C(8)±H and the ꢁ-CH2 of the butanoyl chain of 2 and 3. No equivalent

Fig. 3. (A) Structural drawing of 1 showing the atom numbering scheme (50% probability ellipsoids)
Ê
as observed in its crystal structure; hydrogens are added and have an arbitrary radius of 0.1 A; (B)
packing arrangement of 1 in the crystal

M. T. Huggins and D. A. Lightner: Dimeric Dipyrrinones
209
1
Fig. 4. Selected H{1H} NOEs observed in dipyrrinones in CDCl3; strong NOEs are indicated by
curved double headed arrows, weak NOEs by dashed double headed arrows
NOE was seen between the C(8)±CH3 and the ꢁ-CH2 of the butanoyl chain of 1. In
4, an NOE was measured between the formyl hydrogen and the pyrrole NH. These
data suggest a conformational preference for the 9-ketone or aldehyde carbonyl
group anti to the pyrrole NH in 1 and 4 and syn to the pyrrole NH in 2 and 3.
Evidence for dimer formation can be found in the weak NOEs between the C(2)
methyl group and remote hydrogens, as reported previously in 9-H- and 9-CH3-
dipyrrinones such as 5 [8c]. An NOE between the C(2) methyl and the ꢁ-CH2 of the
fused cyclohexanone ring also con®rms dimer formation for 10 in CDCl3. Similarly,
the NOE seen between the C(2)-methyl and the formyl proton of 4 is compatible
with the presence of planar, intermolecularly hydrogen-bonded dimers. In summary,
the NOE data are consistent with an intramolecularly hydrogen-bonded dimer in
CDCl3 for 4 and 10 analogously to 5 (Fig. 2A), but we could ®nd no NOE evidence
for dimers in 1±3.
Dipyrrinone dimers may also be detected from an examination of their NH
chemical shifts. Typical dipyrrinones exhibit rather different NH 1H NMR chemical
shifts in (CD3)2SO and CDCl3. Thus, kryptopyrromethenone (5) shows lactam and
pyrrole NH chemical shifts of 9.83 and 10.22 ppm in (CD3)2SO, probably due to
hydrogen bonding to the solvent [1, 8b]. In contrast, the NH chemical shift of the
lactam NH is strongly deshielded by ꢀ2 ppm (to ꢀ11.42 ppm) in CDCl3, a solvent
in which 5 is known to be an intermolecularly hydrogen-bonded dimer (Fig. 2A) [1,
6a]. Similar sets of lactam and pyrrole NH chemical shifts are found in the 1H NMR
spectra of the simple dipyrrinones 6±9 and 11 (Table 2), suggesting a similar
behavior: hydrogen-bonded dimers in CDCl3, monomers hydrogen-bonded to the
solvent in (CD3)2SO. In further distinction, and consistent with dipyrrinone
monomers hydrogen-bonded to the solvent in (CD3)2SO, the monomer of 5 in
CDCl3 exhibits strongly shielded pyrrole (8.10 ppm) and lactam (7.75 ppm) NH
chemical shifts [8c].

210
M. T. Huggins and D. A. Lightner
1
Table 2. Solvent dependence of lactam and pyrrole NH chemical shifts in the H NMR spectra of
dipyrrinonesa
1H NMR chemical shifts (ꢂ/ppm)
DMSO-d6
CDCl3
R1
R2
R3
R4
R5
Lactam
Pyrrole
Lactam
Pyrrole
1
2
3
4
5
6
7
8
9
Me
Et
Me Me
Me
H
n-PrCO
n-PrCO
n-PrCO
CHO
Me
10.36
10.49
10.50
10.57
9.83
10.74
11.31
11.31
10.96
10.22
10.48
10.99
10.74
10.72
11.35
10.45
8.65
9.28
9.33
10.05
10.09
10.91
10.44
10.41
10.54
10.67
10.63
11.09
10.23
Et
Et
Me
Me
Me
Me
Me
Me
Et
H
9.65
Me Et
Et
Et
Et
H
10.69
11.42
11.05
10.71
11.13
11.09
10.52
10.90
Et
Me
Me Et
H
9.72
Et
Et
Et
H
H
9.59
Et
Me
Me
H
H
9.76
Me
H
H
9.76
10 Me
11 Me
Me Me
Me Me
(CH2)3 COb
10.41
9.71
Me
H
a
2
For ꢀ10 M solutions at 25ꢁC; chemical shifts (ꢂ) are reported in ppm down®eld from (CH3)4Si and
referenced to residual non-deuterated solvent: 7.26 ppm, CHCl3 and 2.49 ppm, DMSO; assignments
are derived from HMBC, 1H{1H} NOE, or homonuclear decoupling experiments; b bridged from C(8)
to C(9)
There is remarkable consistency in the NH chemical shifts of dipyrrinones 5±9
and 11 in CDCl3: a lactam NH signal near 11 ppm and a pyrrole NH signal near
10.5 ppm. The data are consistent with a dimer. In contrast, the lactam NH chemical
shifts in (CD3)2SO are shielded to ꢀ 9.7 ppm, whereas the pyrrole NH signals
remain near 10.5 ppm. The data are consistent with monomeric dipyrrinones
hydrogen-bonded to the solvent.
Acylation at C(9) causes the dipyrrinone NH chemical shifts (in (CD3)2SO) to
become somewhat more deshielded than those of the 9-H-dipyrrinones: down to
ꢀ11 ppm for the pyrrole NH and to ꢀ10.5 ppm for the lactam. The deshielding can
be attributed to the carbonyl attached to C(9), since the presence of an alkyl group
(as in 5) has little effect. A wider spread of chemical shift values is seen CDCl3
where dimers tend to be favored. Thus, both the pyrrole and lactam NHs are found
to fall in wide ranges: between 9.3 and 11.1 ppm for the pyrrole NHs and between
8.7 and 10.7 ppm for the lactams. The wide range of pyrrole chemical shifts might
be attributed to the orientation of the carbonyl at C(9) relative to the pyrrole NH.
The in¯uence of carbonyl group orientation has been reported earlier for ꢁ-acylated
monopyrroles [11], where the anti-orientation led to a more shielded pyrrole NH
than the syn-orientation. In 10, the carbonyl group attached to C(9) is ®xed in syn-
orientation. In 1, the carbonyl also appears to be anti, based on the NOE data, and
thus indicates that it is perhaps the syn-orientation of the ketone ꢁ-CH2 that shields
the pyrrole NH. On the basis of the monopyrrole studies, one is tempted to conclude

Dimeric Dipyrrinones
211
that the 9.33 ppm chemical shift of the pyrrole NH of 1 can be attributed to the acyl
group oriented anti to the pyrrole NH, whereas in 2±4 it is syn.
Homoassociation measured by vapor pressure osmometry
Given the fact that 1 is present in the crystal as an intermolecularly hydrogen
bonded dimer, but apparently as a monomer in chloroform (a solvent where dipyr-
rinones are known to be dimeric [1, 6]), we investigated possible dimer formation in
chloroform solutions of 1±11 by vapor pressure osmometry (VPO). Previously it
1
had been shown by VPO [1, 6] and by H NMR analysis [8b,c] that kryptopyr-
romethonone (5) is present largely as an intermolecularly hydrogen-bonded dimer
in chloroform. The simple 9-H-dipyrrinones 6±9 are no exception and give
molecular weights corresponding to dimers (Table 3). Similarly and consistent with
the NOE data (Fig. 4), 4 and 10 also show molecular weights pointing to dimers. In
contrast, however, VPO measurements of 1±3 clearly indicate mainly monomers in
chloroform. Thus, whereas 1 is a dimer in the crystal, it is monomeric in solution,
and the latter explains its unusually shielded NH chemical shifts observed in CDCl3.
1
Homoassociation constants from H NMR measurements
The VPO studies (Table 3) indicated a slight extent of dimer formation in 9-acyl-
dipyrrinone 2. An examination of concentration dependence of the dipyrrinone NH
chemical shifts in CDCl3 over the temperature range from 60 to ‡60ꢁC shows
considerable variation (Fig. 5, left). The sets of curves for the pyrrole NH show a
clear plateau (at 10.87 ppm) at 60ꢁC in the high concentration region and a second
Table 3. Molecular weights of dipyrrinones in CHCl3a
Formula
weight
Measured
molecular
weight
(g/mol)
(g/mol)
R1
R2
R3
R4
R5
1:
2:
Me
Et
Me
Et
Me
Me
Me
Et
Me
H
n-PrCO
n-PrCO
n-PrCO
CHO
Me
286
300
286
272
258
244
216
230
216
270
301Æ10
370Æ15
379Æ15
550Æ15
509Æ20
448Æ25
378Æ20
453Æ20
428Æ25
504Æ25
3:
Me
Me
Me
Me
Et
Et
H
4:
Me
Et
Et
5:
Me
Et
Et
6:
Me
Et
Et
H
7:
H
H
H
8:
Et
Et
Me
Me
Me
H
H
9:
10:
Me
Me
Et
H
H
COb
Me
(CH2)3
a
At 45ꢁC, dipyrrinone concentration range from 2.0 to 12:8 Â 10 3 mol/kg, calibrated using benzil
b
(formula wt. 210, measured molecular wt. 220 Æ 15 g/mol; bridged from C(8) to (9)

212
M. T. Huggins and D. A. Lightner
Table 4. Dipyrrinone NH chemical shifts and thermodynamic parametersa for homoassociation of 2
Parameter
Lactam-NH
Pyrrole-NH
ꢂM (ppm)
ꢂD (ppm)
7.17
10.58
638
8.89
10.87
625
1
Ka ( 25ꢁC, M
)
1
Ka (0ꢁC, M
Ka (25ꢁC, M
)
1
228
196
)
63.0
28.0
14.2
10.5
63.7
28.4
14.3
10.5
ÁHꢁ (kJ/mol)
ÁSꢁ (e.u.)
ÁGꢁ (kJ/mol)
a
ÁHꢁ and ÁGꢁ: Æ2:1 kJ/mol, ÁSꢁ: Æ1:0 e.u.; all plots (Fig. 6) have R-values above 0.99
1
Fig. 5. Behavior of the pyrrole (upper) and lactam (lower) NH H NMR chemical shifts between
60ꢁC and ‡60ꢁC over a concentration range from 1:66  10 2 M to 1:30  10 4 M; left: ꢂNH vs.
logarithm of initial concentration of monomeric dipyrrinone; right: logꢂꢂobs ꢂMo† 2logꢂꢂD ꢂobs
vs. logarithm of initial concentration of monomeric dipyrrinone from 25ꢁC to ‡25ꢁC
†

Dimeric Dipyrrinones
213
Fig. 6. van't Hoff plot for 9-acyl-dipyrrinone 2, with Kassoc determined from the temperature and
concentration dependence of the pyrrole and lactam NH chemical shifts
plateau at 8.89 ppm at ‡60ꢁC in the dilute concentration range. These data are
consistent with ꢂmonomer ˆ 8:89 and ꢂdimer ˆ 10:87 ppm. Observing the curves for
the lactam NHs gives a plateau at 7.17 ppm (monomer) at ‡60ꢁC, and we assume a
second one at 10.58 ppm and 60ꢁC for the dimer. From these data, and assuming a
simple monomer-dimer equilibrium (K ˆ ‰DimerŠ=‰MonomerŠ2), by plotting
logꢂꢂobs ꢂmonomer
†
2logꢂꢂdimer† vs. log[sample] [8c] we obtain straight-line plots
for three temperatures (Fig. 5, right). From such plots, one obtains K at each
temperature. Plots of lnK vs. 1/T for the pyrrole and the lactam NH data give
straight-line plots (Fig. 6) from which various thermodynamic parameters (Table 4)
1
may be attained. As expected, the dimerization constant is small (K ꢀ 60 M ) at
1
room temperature, and ÁS is negative. In contrast, K is ꢀ 23000 M
for
kryptopyrromethenone [8c], and thus we assumed similarly large K values for
dipyrrinones 4±11.
Unless the acyl carbonyl group is constrained to adopt a syn-orientation with
respect to the dipyrrinone's pyrrole NH, as in 10, it prefers the anti-orientation when
a C(8)-alkyl is present. This apparently alleviates an unfavorable nonbonded steric
buttressing between the ketone ꢁ-CH2 and the C(8)-alkyl when the acyl carbonyl is
oriented syn, as in 1. In the anti-orientation, the ketone ꢁ-CH2 is oriented in such a
way as to inhibit intermolecular hydrogen bonding. Only the special circumstances
of crystal packing cause 1 to adopt the anti-conformation and thereby achieve
intermolecular hydrogen bonding. In 2, which has no C(8)-alkyl group, the NOE
data of Fig. 4 indicate a preference for the syn-orientation, and from a K of ca.
60 M 1 for the dimerization of 2 one can anticipate about 20% of dimer (and, thus,
2
mainly monomer) from an initial concentration of 10 M 2 at 25ꢁC. Here, strong
dimerization may be prevented by a modest steric repulsion between the C(2)-alkyl
and the C(10)-carbonyl.

214
M. T. Huggins and D. A. Lightner
Table 5. Comparison of dipyrrinone UV/Vis spectroscopic dataa
Compoundb
Solvent
C6H6
R1
R2
R3
R4
M
R5
B
CHCl3
CH3OH
CH3CN
(CH3)2SO
M
M
M
1
412 (14800)s 412 (18200)s 411 (22400) 404 (19400)s 415 (21800)
392 (20500) 392 (23700) 392 (28000) 384 (26000) 394 (26200)
415 (15400)s 410 (17900)s 415 (25500) 406 (19000)s 420 (24500)
393 (22400) 391 (24100) 393 (30600) 385 (26200) 396 (28500)
418 (20500) 415 (20400)s 414 (22900) 403 (18500)s 418 (26800)
395 (25900) 395 (26700) 392 (27700) 384 (25200) 395 (30500)
423 (26300) 416 (19400)s 415 (28200) 408 (22300)s 420 (29000)
400 (30900) 397 (25700) 395 (31900) 389 (27700) 398 (31500)
411 (36200) 407 (33500) 416 (33700) 403 (30000) 413 (25800)
E
E
M
2
H
H
E
E
E
H
H
B
M
M
M
M
E
E
M
3
B
M
E
E
F
4
M
5
M
H
H
H
M
E
E
394 (29400) 389 (25400) 398 (22000) 384 (29700) 395 (28600)
387 (30600) 384 (29800) 390 (32700) 376 (28900) 384 (31200)
387 (30200) 381 (29400) 389 (32400) 374 (28300) 385 (29900)
6
M
8
M
M
M
E
M
9
M
M
M
10
M
11
(CH2)3 CO
420 (22200) 413 (16400)s 415 (24200) 405 (19200)s 419 (25600)
397 (27500) 393 (22700) 393 (28000) 386 (24800) 396 (27400)
392 (23500) 394 (25300) 396 (27200) 395 (26700) 395 (26300)
M
H
a
b
s
ꢅ nm (ꢆ/dm3 Á mol 1); M ˆ Me, E ˆ Et, B ˆ butanoyl, F ˆ formyl; shoulder
UV/Vis comparisons
(4Z)-Dipyrrinones typically show UV/Vis maxima in the region of 380±420 nm,
depending on the location, type, and number of substituents. The absorption band
Ã
is typically intense (" ꢀ 30000) as might be expected for a ꢄ±ꢄ type excitation.
With fewer alkyl substituents (as in 8 and 9), ꢅmax is hypsochromically shifted;
with more alkyl substituents (as in 5, 6, and 11), a bathochromic shift is observed.
Peralkylated (4Z)-dipyrrinones, e.g. 5, tend to have ꢅmax near 410 nm and larger
ꢆ values. With an acyl or formyl substituent at C(9), as in 1±4 and 10, two distinct
maxima of roughly equal intensity appear between 390 and 425 nm in all solvents
studied. The two bands are not due to an exciton, as there is little evidence for
dimer formation. It is also apparently not due to rotational isomers about the acyl
or formyl group, since 10 also exhibits two ꢅmax, and its acyl group is constrained
to the syn-orientation. The data suggest the emergence of a second long-
wavelength electronic transition to complement that seen in simpler dipyrrinones
[1], but the spectroscopic characterization of the new transition is currently
unknown. In view of its intensity, the corresponding transition dipole presumably
lies along the length of the molecule.
Experimental
All UV/Vis spectra were recorded on a Perkin-Elmer ꢅ-12 spectrophotometer. Vapor pressure
osmometry (VPO) measurements were performed using an Osmomat 070 (Gonotec, Berlin,

Dimeric Dipyrrinones
215
Germany) in CHCl3 (from Allied, with amylene stabilizer) at 45ꢁC; benzil was used for calibration.
NMR spectra were obtained on GE QE-300 or GE GN-300 spectrometers operating at 300 MHz, or
on a Varian Unity Plus 500MHz spectrometer in CDCl3 unless otherwise speci®ed. Chemical shifts
are reported in ppm and referenced to the residual CHCl3 1H signal at 7.26 ppm and the 13C signal at
77.0 ppm. HMQC and HMBC spectra were used to assign 13C NMR chemical shifts. Melting points
were taken on a Mel Temp capillary apparatus and are uncorrected. Combustion analyses were carried
out by Desert Analytics, Tucson, AZ; their results agreed with the calculated values within
experimental error. Analytical thin layer chromatography was carried out on J.T. Baker silica gel IB-F
plates (125 m layer), ¯ash column chromatography on Woelm silica gel F, thin layer chromatography
grade. Radial chromatography was performed on Merck Silica Gel PF254 with gypsum preparative
layer grade using a Chromatotron (Harrison Research, Inc., Palo Alto, CA). Spectroscopic data were
obtained in spectral grade solvents. Deuterated solvents were purchased from Cambridge Isotope
Labs, ceric ammonium nitrate from Alfa Aesar. CH2Cl2, MeOH, acetic acid, THF, hexane, AlCl3, and
2-propanol were from Fisher, butanoyl chloride was obtained from Acros.
2,3,7,8-Tetramethyl-(10H)-dipyrrin-1-one (11) [10], 2,3-dimethyl-7,8-diethyl-(10H)-dipyrrin-1-
one (6) [12], 2,3-dimethyl-7,8-diethyl-(10H)-dipyrrin-1-one-9-carboxylic acid (14) [12], and 2,3-
diethyl-(10H)-dipyrrin-1-one (7) [9] were prepared by literature methods. 4-Carboethoxy butanoyl
chloride was readily prepared from the reaction of ethyl hydrogen glutarate with SOCl2 as a modi®ed
procedure from Ref. [13].
2,3,4,8-Tetramethyl-9-butanoyl-(10H)-dipyrrin-1-one (1; C17H22N2O2)
To a 500cm3 round bottomed ¯ask equipped with magnetic stirring, 0.200 g (0.9 mmol) of 3,4,7,8-
tetramethyl-(10H)-dipyrrinone (11) [10] and 150 cm3 of CH2Cl2 were added. The solution was stirred
in an ice bath for 20 min. A solution of 2 cm3 of acid chloride and 4.0 g of AlCl3 in 100cm3 of
CH2Cl2 was added all at once, the reaction mixture was stirred for 2 h at room temperature, poured
onto concentrated HCl/ice (200 cm3/100g), and stirred for further 2 h. The organic layer was
separated, and the aqueous layer was extracted twice with 100cm3 CH2Cl2. The combined extracts
were washed with saturated aqueous NaHCO3 solution (2 Â 200 cm3), water (400 cm3), and dried
over anhydrous Na2SO4. The solvent was removed, and the crude product was puri®ed by radial
chromatography (MeOH:CH2Cl2 ˆ 97:3) and recrystallized from CH2Cl2/hexane to give pure 1.
Yield: 92 mg (35%); m.p.: 225±226ꢁC; IR (KBr): ꢇ ˆ 3341, 2956, 2920, 1668, 1640, 1436, 1385,
1297, 1234, 1169, 943, 728, 695 cm 1; 1H NMR (CDCl3, ꢂ, 500 MHz): 0.99 (t, 7.5 Hz, 3 H), 1,70 (p,
7.5 Hz, 2 H), 1.93 (s, 3 H), 2.07 (s, 3 H), 2.11 (s, 3 H), 2.31 (s, 3 H), 2.78 (t, 7.5 Hz, 2 H), 5.94 (s, 1 H),
1
8.65 (s, 1 H), 9.33 (s, 1 H) ppm; H NMR (DMSO-d6, ꢂ, 300 MHz): 0.93 (t, 7.5 Hz, 3 H), 1.60 (p,
7.5 Hz, 2 H), 1.78 (s, 3 H), 2.01 (s, 3 H), 2.07 (s, 3 H), 2.22 (s, 3 H), 2.79 (t, 7.5 Hz, 2 H), 5.95 (s, 1 H),
10.36 (s, 1 H), 10.74 (s, 1 H) ppm; 13C NMR: Table 1; UV/Vis: Table 4.
2,3-Diethyl-7-methyl-9-butanoyl-(10H)-dipyrrin-1-one (2; C18H24N2O2)
2 was prepared from 0.30 g (1.3 mmol) of 2,3-diethyl-7-methyl-(10H)-dipyrrin-1-one (8) following
the same procedure as for 1.
Yield: 194 mg (50%); m.p.: 149±150ꢁC; IR (KBr(: ꢇ ˆ 3337, 2967, 2927, 1700, 1673, 1652, 1458,
1416, 1297, 1250, 1163, 1057, 1023cm 1; 1H NMR (CDCl3, ꢂ, 500 MHz): 0.96 (t, 7.0Hz, 3 H), 1.13
(t, 7.5 Hz, 3 H), 1.22 (t, 7.0 Hz, 3 H), 1.71 (m, 2 H), 2.19 (s, 3 H), 2.45 (q, 7.5 Hz, 2 H), 2.55 (q, 7.0Hz,
2 H), 2.76 (t, 4.0 Hz, 2 H), 5.97 (s, 1 H), 6.77 (d, 1.5Hz, 1 H), 9.88 (s, 1 H), 10.36 (s, 1 H) ppm;
1H NMR (DMSO-d6, ꢂ, 300 MHz): 0.90 (t, 7.0Hz, 3 H), 1.02 (t, 7.5 Hz, 3 H), 1.11 (t, 7.5Hz, 3 H),
1.60 (p, 7.0 Hz, 2 H), 2.12 (s, 3 H), 2.27 (q, 7.5Hz, 2 H), 2.51 (q, 7.5Hz, 2 H), 2.69 (t, 7.0 Hz, 2 H),
5.91 (s, 1 H), 2.88 (d, 3.0Hz, 1 H), 10.49 (s, 1 H), 11.31 (s, 1 H) ppm; 13C NMR: Table 1; UV/Vis:
Table 4.

216
M. T. Huggins and D. A. Lightner
2,7-Dimethyl-3-ethyl-9-butanoyl-(10H)-dipyrrin-1-one (3; C16H20N2O2)
3 was prepared from 0.15 g (0.69 mmol) of 2,7-dimethyl-3-ethyl-(10H)-dipyrrin-1-one (9) following
the same procedures as for 1.
Yield: 0.104 g (53%); m.p.: 249±250ꢁC; IR (KBr): ꢇ ˆ 3331, 2961, 2867, 1654, 1454, 1378, 1292,
1248, 1165, 1053, 981, 818, 766, 669 cm 1; 1H NMR (CDCl3, ꢂ, 500MHz): 0.96 (t, 75 Hz, 3 H), 1.19
(t, 7.5 Hz, 3 H), 1.71 (sextet, 7.5 Hz, 2 H), 1.99 (s, 3 H), 2.18 (s, 3 H), 2.54 (q, 7.5 Hz, 2 H), 2.74 (t,
7.5 Hz, 2 H), 5.97 (s, 1 H), 6.77 (d, 2 Hz, 1 H), 9.65 (s, 1 H), 10.85 (s, 1 H) ppm; 1H NMR (DMSO-d6,
ꢂ, 300 MHz): 0.90 (t, 7.5 Hz, 3 H), 1.09 (t, 7.0 Hz, 3 H), 1.79 (s, 3 H), 2.12 (s, 3 H), 2.51 (q, 7.5 Hz,
2 H), 2.69 (t, 7.0 Hz, 2 H), 5.92 (s, 1 H), 6.89 (d, 2.5 Hz, 1 H), 10.50 (s, 1 H), 11.31 (s, 1 H) ppm; 13C
NMR: Table 1; UV/Vis: Table 4.
2,3-Dimethyl-7,8-diethyl-(10H)-dipyrrinone-9-aldehyde (4; C16H20N2O2)
To a 200 cm3 round bottomed ¯ask equipped with magnetic stirring, 1.8 g (6.3 mmol) of dipyrrinone
carboxylic acid (14) and 40 cm3 of TFA were added. The reaction mixture was stirred for 30 min at
room temperature followed by cooling to 0ꢁC in an ice/salt bath. 5 cm3 triethyl orthoformate were
added dropwise followed by stirring for 10 min. The reaction mixture was then poured onto 100 g
ice/water and stirred for 30 min. The crude product was collected by vacuum ®ltration and puri®ed
by trituration with cold CH2Cl2 to give pure 4.
Yield: 1.4 g (82%); m.p.: 256±257ꢁC; IR (KBr): ꢇ ˆ 3338, 2970, 2903, 1708, 1687, 1658, 1601,
1558, 1463, 1252, 1175, 756, 696 cm 1; 1H NMR (CDCl3, ꢂ, 300 MHz): 1.17 (t, 7.5 Hz, 3 H), 1.26 (t,
7.5 Hz, 3 H), 2.00 (s, 3 H), 2.13 (s, 3 H), 2.57 (q, 7.5 Hz, 2 H), 2.78 (q, 7.5 Hz, 2 H), 5.96 (s, 1 H), 9.70
(s, 1 H), 10.69 (s, 1 H), 10.91 (s, 1 H) ppm; 1H NMR (DMSO-d6, ꢂ, 300 MHz): 1.05 (t, 7.5 Hz, 3 H),
1.07 (t, 7.5 Hz, 3 H), 1.79 (s, 3 H), 2.07 (s, 3 H), 2.50 (q, 7.5 Hz, 2 H), 2.67 (q, 7.5 Hz, 2 H), 5.90 (s,
1 H), 10.57 (s, 1 H), 10.96 (s, 1 H), 12.36 (s, 1 H) ppm; 13C NMR: Table 1; UV/Vis: Table 4.
2,3-Diethyl-7-methyl-(10H)-dipyrrin-1-one (8; C14H18N2O)
3-Methyl-2-formyl-5-carboethoxy-(1H)-pyrrole (15, 4.2 g, 23 mmol), 3,4-ethyl-1H-pyrrol-2-one [14]
(3.2 g, 23 mmol), and 50 cm3 of methanol were placed in a 500 cm round bottomed ¯ask equipped
with magnetic stirring. 200cm3 of 4 M aqueous KOH were added, and the reaction mixture was
heated at re¯ux for 6 h and then chilled in an ice bath for 30 min. After acidi®cation with concentrated
HCl to pH ꢀ3, the resultant solid product (12) was collect by ®ltration (vacuum), washed with
100 cm3 of water, and dried in vacuo. The resulting powder was placed in a 500 cm3 round bottomed
¯ask and mixed with 5.0 g of potassium acetate and 5.0 g of sodium acetate trihydrate which had been
ground with mortar and pestle until intimately mixed. The solid mixture was heated to ca. 160ꢁC at
which time it melted with the evolution of CO2. The temperature was maintained at 160ꢁC until the
evolution of CO2 ceased (ca. 10 min). The reaction mixture was cooled to room temperature, and
400 cm3 of water were added followed by vigorous stirring for 1 h. The product was collect by
®ltration (vacuum) and triturated with 50 cm3 cold acetone to give pure 8.
Yield: 1.75 g (50%); m.p.: 206±208ꢁC; IR(KBr): ꢇ ˆ 3356, 2969, 2920, 1657, 1557, 1464, 1372,
1265, 1178, 1102, 1057, 1017, 946, 739, 675 cm 1; 1H NMR (CDCl3, ꢂ, 500 MHz): 1.18 (t, 7.50 Hz,
3 H), 1.20 (t, 7.50 Hz, 3 H), 2.23 (s, 3 H), 2.41 (q, 7.5 Hz, 2 H), 2.56 (q, 7.5 Hz, 2 H), 6.11 (dd, 1.5 Hz,
3.0 Hz, 1 H), 6.17 (s, 1 H), 6.97 (dd, 3.0 Hz, 3.0 Hz, 1 H), 10.67 (s, 1 H), 11.13 (s, 1 H) ppm; 1H NMR
(DMSO-d6, ꢂ, 300 MHz): 1.10 (t, 7.5 Hz, 3 H), 1.10 (t, 7.5 Hz, 3 H), 2.11 (s, 3 H), 2.23 (q, 7.5 Hz, 2 H),
2.50 (q, 7.5 Hz, 2 H), 5.96 (s, 1 H), 5.99 (dd, 1.5 Hz, 3.0 Hz, 1 H), 6.99 (t, 3.0 Hz, 1 H), 9.76 (s, 1 H),
10.74 (s, 1 H) ppm; 13C NMR: Table 1; UV/Vis data: Table 4.
2,7-Dimethyl-3-ethyl-(10H)-dipyrrin-1-one (9; C14H18N2O)
9 was prepared from 1.6 g (8.9 mmol) of 3-methyl-2-formyl-5-carboethoxy-(1H)-pyrrole (15) and
0.91 g (0.93 mmol) of 3-methyl-4-ethylpyrrolin-2-one [15] following the same procedure as for 8.

Dimeric Dipyrrinones
217
Yield: 0.58 g (53%); m.p.: 201±202ꢁC; IR (KBr): ꢇ ˆ 3354, 3167, 3092, 2970, 2922, 1668, 1632,
1470, 1377, 1264, 1177, 1059, 747, 672 cm 1; 1H NMR (CDCl3, ꢂ, 300 MHz): 1.19 (t, 7.5 Hz, 3 H),
1.95 (s, 3 H), 2.23 (s, 3 H), 2.55 (q, 7.5 Hz, 2 H), 6.12 (dd, 2.5 Hz, 1.5 Hz, 1 H), 6.17 (s, 1 H), 7.00 (t,
1
2.5 Hz, 1 H), 10.63 (s, 1 H), 11.02 (s, 1 H) ppm; H NMR (DMSO-d6, ꢂ, 300 MHz): 1.08 (t, 7.5 Hz,
3 H), 1.78 (s, 3 H), 2.11 (s, 3 H), 2.51 (q, 7.5 Hz, 2 H), 5.97 (s, 1 H), 6.00 (dd, 2.5 Hz, 1.5 Hz, 1 H),
6.89 (t, 2.5 Hz, 1 H), 9.76 (s, 1 H), 10.72 (s, 1 H) ppm; 13C NMR: Table 1; UV/Vis: Table 4.
3,4-Dimethyl-5-(3-methyl-4,5,6,7-tetrahydro-7-oxo-indolinyl-2-methylidene)-3-pyrrolin-2-one
(10; C16H22N2O3)
To a 25 cm3 round bottomed ¯ask equipped with magnetic stirring, 50 mg of 2,3,7-trimethyl-8-(4-
carbomethoxypropyl)-(10H)-dipyrrin-1-one (19) and 10 cm3 of tri¯uoroacetic acid were added and
the mixture was heated at re¯ux for 1 h. It was then cooled in an ice bath to 0ꢁC, and 25 cm3 of cold
water were added to yield a yellow-green precipitate. The solid was collected by ®ltration and puri®ed
by radial chromatography (CH2Cl2:MeOH ˆ 97:3) to give the desired product after removal of the
solvent.
Yield: 27 mg (60%); m.p.: 247±248ꢁC (dec); IR (®lm): ꢇ ˆ 3273, 2917, 1698, 1659, 1590,
1461 cm 1; 1H NMR (CDCl3, ꢂ, 500 MHz): 1.98 (s, 3 H), 2.13 (m, 5 H), 2.17 (s, 3 H), 2.66 (t, 6.0 Hz,
1
2 H), 2.76 (t, 6.0 Hz, 2 H), 5.96 (s, 1 H), 10.52 (s, 1 H), 11.09 (s, 1 H) ppm; H NMR (DMSO-d6, ꢂ,
300 MHz): 1.78 (s, 3 H), 2.00 (p, 6.0 Hz, 2 H), 2.04 (s, 3 H), 2.07 (s, 3 H), 2.38 (t, 6.0 Hz, 2 H), 2.57
‡
(t, 6.0 Hz, 2 H), 5.92 (s, 1 H), 10.41 (s, 1 H), 11.35 (s, 1 H) ppm; ESI-MS:m/z ˆ 271.2 [M ] (calcd.:
272.2); 13C NMR: Table 1; UV/Vis: Table 4.
2,3-Dimethyl-5-(ethoxycarbonyl)-(1H)-pyrrole-4-butyric acid ethyl ester (22; C15H23NO4)
To a 1 dm3 round bottomed ¯ask equipped for magnetic stirring, 15.34 g of magnesium shavings,
3.2 cm3 of CCl4, and 166 cm3 of absolute ethanol were added. The mixture was heated at re¯ux for 4 h
to form magnesium ethoxide. The excess ethanol was removed (rotovap), and 370 cm3 of anhydrous
diethyl ether were added and the reaction mixture was cooled to 15ꢁC. 3-Methyl-2,4-pentanedione
[16] (70.07 g (0.614 mol)) was added with magnetic stirring, and the mixture was stirred at room
temperature for 3 h followed by 1 h of heating at re¯ux. The reaction mixture was transferred to a
2 dm3 3-neck round bottomed ¯ask equipped with a mechanical stirrer, an addition funnel, and a
thermometer. A solution of 123.3 g (0.69 mol) of 4-carboethoxy butanoyl chloride and 125cm3 of
anhydrous diethyl ether were placed in the addition funnel, and the reaction mixture was cooled to
10ꢁC. The solution was added dropwise to the reaction mixture with continued cooling. After the
addition was complete, the mixture was slowly warmed to room temperature and stirred for 4 h. The
reaction mixture was cooled in ice bath and acidi®ed with 50 cm3 of 25% aqueous H2SO4. The
biphasic reaction mixture was then decanted from the magnesium salts which were washed with
150 cm3 of diethyl ether. Both the ether wash and the reaction mixture were combined, and the
organic layer was separated. The ether solution was washed with 10% aqueous NaOH (2 Â 200 cm3)
and saturated aqueous NaCl (2 Â 100 cm3) and dried over anhydrous MgSO4. The ether was then
removed by rotary evaporation to afford 23.
The residual oil and 500 cm3 of glacial acetic acid were transferred to a 2 dm3 3-neck round
bottomed ¯ask equipped with a mechanical stirrer, addition funnel, and thermometer. The solution
was heated to ꢀ80ꢁC, and 125 g of anhydrous sodium acetate and 106 g of zinc dust were added all
at once. The reaction mixture was then heated to ꢀ95ꢁC, and a solution of 95 g (0.5 mol) diethyl
oximinomalonate [17], 150 cm3 acetic acid, and 50 cm3 H2O was placed in the addition funnel and
added to the reaction mixture such that the temperature was maintained between 100±110ꢁC. After
the addition was complete, the reaction mixture was heated at re¯ux for 2.5 h. The hot reaction
mixture was poured into 2 dm3 of ice water with stirring. The solution was placed in a cold room for
24 h, and the solid product was collected by ®ltration and recrystallized from EtOH/H2O.

218
M. T. Huggins and D. A. Lightner
Yield: 25.8 g (20%); m.p.: 64±65ꢁC; IR (thin ®lm): ꢇ ˆ 3310, 2979, 2934, 1736, 1663, 1501,
1
1438, 1268, 1172, 1111, 1025 cm 1; H NMR (CDCl3, ꢂ, 500 MHz): 1.24 (t, 7.0 Hz, 3 H), 1.34 (t,
7.0 Hz, 3 H), 1.84 (p, 7.5 Hz, 2 H), 1.92 (s, 3 H), 2.17 (s, 3 H), 2.32 (t, 7.5 Hz, 2 H), 2.75 (t, 7.5 Hz,
2 H), 4.11 (q, 7.0 Hz, 2 H), 4.28 (q, 7.0 Hz, 2 H), 8.61 (s, 1 H) ppm; 13C NMR (CDCl3, ꢂ, 125 MHz):
8.70, 11.42, 14.23, 14.51, 24.48, 25.75, 33.94, 59.60, 60.17, 116.50, 116.75, 129.63, 131.02, 161.42,
173.81 ppm.
2-Formyl-3-methyl-5-(ethoxycarbonyl)-1H-pyrrole-4-butyric acid ethyl ester (21; C15H23NO5)
To a 1 dm3 round bottomed ¯ask equipped with magnetic stirring, 2.1 g (7.5 mmol) of 2,3-dimethyl-5-
(ethoxycarbonyl)-(1H)-pyrrole-4-butyric acid ethyl ester (22), 60 cm3 of THF, 120 cm3 of acetic acid,
and 100cm3 of H2O were added. The reaction mixture was placed in an ice bath for 30 min, 16.6 g
ceric ammonium nitrate (30.0 mmol) were added all at once, and the reaction mixture was stirred at
room temperature for 1 h. The reaction mixture was extracted with CH2Cl2 (3 Â 150 cm3), and the
combined extracts were washed with H2O (3 Â 400 cm3), saturated aqueous NaHCO3 (2 Â 300 cm3),
and dried over anhydrous Na2SO4. The solvent was removed (rotovap), and the oily product was
recrystallized from MeOH/H2O.
Yield: 1.6 g (74%); m.p.: 56±57ꢁC; IR (thin ®lm): ꢇ ˆ 3278, 2984, 2940, 2875, 1728, 1710, 1672,
1462, 1447, 1370, 1253, 1173, 1020, 775, 732 cm 1; 1H NMR (CDCl3, ꢂ, 300MHz): 1.25 (t, 7.0 Hz,
3 H), 1.38 (t, 7.0 Hz, 3 H), 1.85 (p, 7.0 Hz, 2 H), 2.32 (s, 3 H), 2.34 (t, 7.0 Hz, 2 H), 2.79 (t, 7.0 Hz,
2 H), 4.12 (q, 7.0 Hz, 2 H), 4.35 (q, 7.0 Hz, 2 H), 9.47 (bs, 1 H), 9.78 (s, 1 H) ppm; 13C NMR (CDCl3,
ꢂ, 125MHz): 8.36, 14.16, 14.24, 23.47, 25.36, 33.70, 60.22, 60.92, 124.35, 129.79, 130.04, 130.69,
160.52, 173.37, 179.15 ppm.
2,3,7-Trimethyl-8-(4-carboxypropyl)-(10H)-dipyrrin-1-one-9-carboxylic acid (20; C17H20N2O5)
To a 125cm3 round bottom ¯ask equipped with magnetic stirring, 0.52g (1.7 mmol) of 2-formyl-3-
methyl-5-(ethoxycarbonyl)-(1H)-pyrrole-4-butyric acid ethyl ester (21), 0.20 g of 3,4-dimethylpyrro-
lin-2-one [9], and 10 cm3 of MeOH were added. A solution of 5 g of sodium hydroxide in 50 cm3 of
water was added, and the reaction mixture was stirred at room temperature for 14 h. The solution was
acidi®ed with 10% aqueous HCl, and the precipitate was collected by centrifugation and triturated
with MeOH.
Yield: 0.40 g (69%); m.p.: 200±201ꢁC (dec); IR (KBr): ꢇ ˆ 3374, 1672, 1460, 1260, 964,
1
796 cm 1; H NMR (CDCl3, ꢂ, 500 MHz): 1.65 (p, 7.5 Hz, 2 H), 1.75 (s, 3 H), 2.12 (s, 3 H), 2.15 (t,
7.5 Hz, 2 H), 2.46 (s, 3 H), 2.65 (t, 7.5 Hz, 2 H), 5.89 (s, 1 H), 10.42 (s, 1 H), 10.96 (s, 1 H), 12.15 (s,
2 H) ppm; 13C NMR (DMSO-d6, ꢂ, 125 MHz): 8.36, 9.01, 9.56, 23.65, 25.55, 33.26, 96.17, 121.31,
122.34, 126.30, 127.49, 130.04, 134.28, 141.85, 161.99, 172.68, 174.39 ppm.
2,3,7-Trimethyl-8-(4-carbomethoxypropyl)-(10H)-dipyrrin-1-one (19; C17H22N2O3)
To a 125 cm3 round bottom ¯ask equipped with magnetic stirring, 0.99 g of 2,3,7-trimethyl-8-(4-
carboxypropyl)-(10H)-dipyrrin-1-one-9-carboxylic acid (20) and 50 cm3 of MeOH were added. To
this solution, 10 cm3 of 10% H2SO4 were added, and the mixture was heated at re¯ux for 2 h. The
reaction mixture was cooled to room temperature, taken up in 150cm3 of CH2Cl2, washed with
H2O (2 Â 100 cm3), saturated aqueous NaHCO3 (2 Â 100 cm3) and dried over anhydrous Na2SO4.
The solvent was removed (rotovap), and the residue was puri®ed by radial chromatography
(CH2Cl2:MeOH ˆ 97:3) to give the desired ester.
1
Yield: 0.66 g (73%); m.p.: 194±195ꢁC (dec); IR (®lm): ꢇ ˆ 3353, 1733, 1656 cm 1; H NMR
(CDCl3, ꢂ, 500 MHz): 1.88 (p, 7.5 Hz, 2 H), 1.94 (s, 3 H), 2.13 (s, 6 H), 2.37 (t, 7.5 Hz, 2 H), 2.47
(t, 7.5 Hz, 2 H), 3.70 (s, 3 H), 6.12 (s, 1 H), 6.85 (d, 1.5 Hz, 1 H), 10.44 (s, 1 H), 11.04 (s, 1 H) ppm;

Dimeric Dipyrrinones
219
13C NMR (CDCl3, ꢂ, 125 MHz): 8.26, 9.44, 9.96, 9.96, 24.62, 25.49, 33.58, 51.47, 102.24, 121.56,
126.59, 123.82, 124.30, 124.37, 129.48, 142.78, 173.72, 174.16 ppm.
2-Formyl-3-methyl-5-(ethoxycarbonyl)-(1H)-pyrrole (15; C9H11NO3)
To a 500cm3 round bottom ¯ask equipped with magnetic stirring, 7.1 g of 2,3-dimethyl-5-
carboethoxypyrrole (17) [18], 250 cm3 of methanol, and 20 cm3 H2O were added. The reaction
mixture was placed in a ice bath for 30 min, 93.8 g of ceric ammonium nitrate were added all at once,
and stirring was continued at room temperature for 3 h. The reaction mixture was taken up in CH2Cl2
(500 cm3), washed with water (3 Â 400 cm3) and saturated sodium bicarbonate (2 Â 300 cm3), and
dried over anhydrous Na2SO4. The solvent was removed (rotovap) to yield an oily product which was
recrystallized from methanol to give the desired pyrrole aldehyde.
1
Yield: 4.45 g (55%); m.p.: 243±244ꢁC (Ref. [18]: 245±247ꢁC) H NMR (CDCl3, ꢂ, 300MHz):
1.37 (t, 7.5 Hz, 3 H), 2.39 (s, 3 H), 4.35 (q, 7.5 Hz, 2 H), 6.72 (d, 2.0 Hz, 1 H), 9.59 (bs, 1 H), 9.78
‡
(s, 1 H) ppm; GC-MS: m=z ˆ 253 [M ], 224 (100%), 192, 174, 148, 104, 77, 65.
Table 6. Crystallographic data for dipyrrinone 1
Formula Weight
Crystallized from
Temperature (K)
Crystal Size (mm)
Formula
286.37
CDCl3
298(2) K
0:20 Â 0:40 Â 0:24
C17H22N2O2
Space group
Z
P1
2
Ê
Cell dimensions
a ˆ 7:7765 (8) A
Ê
b ˆ 10:2949 (10) A
Ê
c ˆ 11:0329 (10) A
ꢁ ˆ 66:155 (7)ꢁ
ꢃ ˆ 76:741 (10)ꢁ
ꢀ ˆ 87:947 (10)ꢁ
Ê 3
V ˆ 784:74 (13) A
Nr/ꢇ range of Refs. used for cell re®nements
Calc. density dx (g/cm3)
Data collection range
40=10:08 > ꢈ > 24:81
1.212
2:08 < ꢈ < 24:99ꢁ
Scan type/scan range
!/1.2ꢁ
3336
No. of total data recorded
No. of unique data
Weighting Schemea
2679
a ˆ 0:0681
No. obs / no. parameters
Rb1, wRc2 ꢂI > 2ꢉꢂI††
2679/191
R1 ˆ 0:0798; R2 ˆ 0:1456
e.s.d. of C±C bond length
0.007
0.245
all
3
Ê
Highest peak in ®nal ÁF map (e Á A
)
Anisotropic non-H atoms
Isotropic non-H atoms
1
none
ꢊ (MoKꢁ) (mm
)
0.081
0.71073
0.78±0.99
Ê
Radiation (ꢅ (A))
Transmittance factors
2
2
a
1
w
ˆ ꢉ2ꢂF2† ‡ ꢂaP† where P ˆ ꢂFo2 ‡ wFc2†=3; Goodness of Fit (GOOF): ꢂÆꢂwꢂFo2 Fc2† †=
0:5
ꢂM N†† where M is the number of re¯ections and N is the number of parameters re®ned;
2
2
0:5
b
R1 ˆ Æ k Fo j j Fc k =Æ j Fo j; wR2 ˆ ꢂÆꢂwꢂFo2 ‡ wFc2† †=ꢉꢂwꢂF2† ††

220
M. T. Huggins and D. A. Lightner
4
2
3
Ê
Table 7. Atomic cordinates (Â10 ) and equivalent isotropic displacement parameters (A Â 10 ) for
1; U(eq) is de®ned as one third of the trace of the orthogonalized Uij tensor
x
y
z
U(eq)
O(1)
5051(5)
3986(5)
2775(6)
1455(6)
3464(8)
2019(7)
534(7)
11894(4)
4800(4)
10145(4)
6721(4)
11519(6)
12427(5)
11591(5)
10107(5)
8955(6)
7449(5)
6437(6)
5096(6)
5287(5)
4322(6)
14009(5)
12021(5)
6731(6)
3716(5)
2727(5)
1880(5)
290(6)
368(4)
67(1)
78(2)
52(1)
46(1)
55(2)
44(2)
45(2)
43(2)
47(2)
40(1)
46(2)
47(2)
43(2)
52(2)
62(2)
61(2)
63(2)
66(2)
54(2)
69(2)
94(3)
O(2)
2642(5)
784(4)
N(1)
N(2)
2366(4)
185(6)
C(1)
C(2)
348(5)
C(3)
974(5)
C(4)
963(7)
1295(5)
1991(5)
2460(5)
3164(5)
3481(5)
2972(5)
3051(6)
174(6)
C(5)
196(7)
C(6)
50(7)
C(7)
1475(7)
793(8)
C(8)
C(9)
1024(7)
2440(8)
2305(8)
1312(7)
3387(7)
1931(7)
2018(7)
3645(8)
C(10)
C(21)
C(31)
C(71)
C(81)
C(101)
C(102)
C(103)
1344(6)
3508(6)
4266(6)
3624(6)
3456(6)
4072(7)
3123(10)
X-Ray structure determination
Crystals of dipyrrinone 1 were grown by slow evaporation of CDCl3. Suitable crystals were coated
with epoxy cement, mounted on a glass ®ber, and placed on a Siemens P4 diffractomer. Unit cell
parameters were determined by least squares analysis of 25 re¯ections with 22:8 < ꢈ < 25:0 using
Ê
graphite monochromatized MoKꢁ radiation (ꢅ ˆ 0:71073 A). 3336 re¯ections were collected in the
range 2:08 < 2ꢈ < 24:99ꢁ yielding 2679 unique re¯ections (Rint ˆ 0:0417). The data were corrected
for Lorentz and polarization effects and absorption using an empirical model derived from azimuthal
data collections. Crystal data are given in Table 6. Scattering factors and corrections for anomalous
dispersion were taken from a standard source [19].
Calculations were performed using the Siemens SHELXTL PLUS, version 5.03, system of
programs re®ning on F2. The structure was solved by direct methods in the space group P1. The unit
cell contains an ordered array of the molecule with no unusual contacts.
All non-hydrogen atoms (Table 7) were re®ned with anisotropic thermal parameters. Hydrogen
Ê
atom positions were calculated using a riding model with a C±H distance ®xed at 0.96 A and a
thermal parameter of 1.2 times of that of the host carbon atom. The largest peak in the ®nal difference
Ê 3
Ê
map corresponded to 0.245 e /A was located 1.178 A from C(81). Tables of bond lengths, bond
angles, and anisotropic and isotropic displacement parameters have been deposited at the Cambridge
Structural Data File (CDC No. 149741).
Acknowledgements
We thank the U.S. National Institutes of Health (HD-17779) for generous support of this work.
Michael T. Huggins is an R.C. Fuson Graduate Fellow. Special thanks are accorded to Prof. J. H.

Dimeric Dipyrrinones
221
Nelson for assistance with the X-ray crystallographic measurements and to Prof. T. W. Bell for
generous use of the VPO instrument.
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Á
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È
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Received August 22, 2000. Accepted September 5, 2000